It is known that cyclic adenosine-3′,5′-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (Sutherland, Pharmacol. Rev, (1960), 12, 265). Its intracellular hydrolysis to adenosine 5′-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis. The most important role in the control of cAMP (as well as of cGMP) levels is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally, highly variable superfamily of the enzyme; eleven distinct families with more than 25 gene products are currently recognized. Although PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers. Immune cells contain type IV and type III PDE, the PDE IV type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. More recently, distinct classes of PDEs have been recognized (Bervo, TIPS, (1990), 11, 150), and their selective inhibition has led to improved drug therapy (Nicholus, et al. TIPS, 1991, 12, 19). Thus it was recognized that inhibition of PDE IV could lead to inhibition of inflammatory mediator release (Verghese et. al., J. Mol. Cell. Cardiol., 1989, 12 (Suppl.II), S 61).
WO 03/47520 discloses substituted amino methyl factor Xa inhibitors. U.S. Patent Publication No. 2003176421, and EP 1040829 disclose prokinetic agents for treating gastric hypomotility and related disorders. WO 02/50070 discloses piperidine derivatives as subtype-selective N-methyl-D-aspartate antagonists. EP 1251128 discloses cyclohexylamine derivatives as subtype-selective N-methyl-D-aspartate antagonists. WO 00/59902 discloses aryl sulfonyls as factor Xa inhibitors. WO 01/19798 and WO01/19788 disclose novel compounds as factor Xa inhibitors. WO 99/23076, WO 99/23077 discloses indazole bioisostere replacement of catechol in therapeutically active compounds. WO 97/49702 and WO 98/09961 disclose indazole derivatives and their use as inhibitor of phosphodiesterase type IV and production of tumor necrosis factor (TNF). WO 97/48697 discloses substituted azabicyclo compounds and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase. WO 99/57951, U.S. Pat. No. 6,339,099 discloses guanidine mimics as factor Xa inhibitor.